PROJECT SUMMARY HCC is the 5th most common malignancy in the world and the 4th leading cause of cancer death in the US. Resection and transplantation are the sole potentially curative treatments for HCC, but only 10-15% of patients are candidates. Sorafenib and doxorubicin (DOX)-transcatheter arterial chemoembolization (TACE) combination may offer a potent combination maximizing therapeutic outcomes by inhibiting angiogenesis and simultaneously inducing apoptosis. Recent clinical results showed that the median overall survival and the risk of progression or death were significantly improved in sorafenib and DOX-TACE combination. However, sorafenib is currently administered systemically in an oral tablet formulation. Consequent systemic exposures and a lack of tumor specificity leads to side-effects including skin rashes, hand and foot syndrome, diarrhea, and hypertension. Given the commonly intolerable severity of these side- effects, drug dose often must be reduced or administration discontinued altogether (>30% of patients). Our MRI-visible pH triggerd drug eluting microsphere (pH-DEM) platforms offer the potential to increase the efficacy of liver-directed therapies for HCC while reducing systemic exposures via catheter-directed delivery. Quantitative imaging of sorafenib and DOX loaded pH-DEM delivery to liver tumors will be critical to permit early prediction of longitudinal response thus prompting adjustments to individual treatment regimens as needed (additional administrations or adoption of alternative therapies). Through a collaborative project building upon our strengths in nanomedicine, materials, interventional oncology, and radiology, we seek to develop a powerful new approach for image-guided cytostatic sorafenib and cytotoxic DOX delivery to liver tumors. This project will address the following Aims in a well-established rodent model of liver cancer: Aim 1: Characterize the relationship between the synthesis protocols for our MRI-visible pH triggered drug eluting microspheres (pH-DEM) and resulting sorafenib and DOX drug loading and release rates. Aim 2: Determine imaging characteristics of these MRI visible sorafenib and DOX loaded pH-DEM and validate that MRI permits in vivo quantification following transcatheter delivery to liver tumors. Aim 3: Validate that sorafenib and DOX loaded pH-DEM inhibit angiogenesis and tumor growth and that in vivo measurements of pH-DEM delivery are predictive of tumor responses.